Excretion Of Beta 2-microglobulin Research Articles

Circadian rhythm of glomerular filtration rate in normal individuals.

1. In a group of 11 normal individuals we measured glomerular filtration rate (GFR) by inulin clearances and effective renal plasma flow (ERPF) by p-aminohippurate clearances during a period of 24 h and a regimen of bedrest, identical food intake per 3 h and normal sleep/wake and light/dark cycles. 2. All subjects had a circadian rhythm for GFR with a maximum of 122 ml/min (SD 22) in the daytime, a minimum of 86 ml/min (SD 12) at night and with a relative amplitude of 33% (SD 15). 3. ERPF had a circadian rhythm with a similar relative amplitude as the GFR rhythm, but with a different phase. Because of this difference in phase, the calculated filtration fraction (GFR/ERPF) followed a circadian rhythm as well. 4. The circadian rhythms of urine volume and sodium excretion were in phase with the GFR rhythm, but the potassium rhythm had a different phase, probably because urinary potassium is largely derived from tubular secretion. 5. Urinary albumin and beta 2-microglobulin excretion had a circadian rhythm in phase with the GFR rhythm. 6. The highest quantity of sodium, water and beta 2-microglobulin was reabsorbed in the daytime; tubular reabsorption, expressed as percentage of the filtered load (fractional reabsorption), had a rhythm with a reversed phase.

Renal function after autotransplantation with direct pyelocystostomy. Long-term follow-up.

The function of 20 human autologous kidney grafts was studied for 4 to 8 years (mean 5 1/2) after autotransplantation with a direct pyelocystostomy. The indications for the operation were low-grade, low-stage tumour of the renal pelvis and/or ureter, frequently recurrent renal stones and remaining outflow obstruction after pyeloplasty for hydronephrosis. The wide pyelocystostomy implies reflux of urine from the urinary bladder to the renal pelvis but no significant changes were found in glomerular or tubular function, studied with 51Cr-EDTA clearance, 131I-Hippuran renography, analysis of beta 2-microglobulin and total protein excretion in urine, and determination of concentration ability after administration of desmopressin. No increase in the severity or frequency of urinary tract infections was observed.

Potentiation of cadmium nephrotoxicity by acetaminophen.

The possible interactions between acetaminophen and cadmium (Cd) on the kidney were investigated in female Sprague-Dawley rats. Acetaminophen was administered in the food at an average dose of 900 mg/kg and Cd in drinking water at the concentration of 200 ppm. The treatment with acetaminophen and Cd lasted 2 and 10 months, respectively. No interaction between Cd and acetaminophen was observed during the period of their concomitant administration: the increase in albuminuria caused by Cd and acetaminophen was additive, while the tubular impairment caused by acetaminophen (increased beta 2-microglobulinuria and decreased kidney concentrating ability) was not exacerbated by Cd. None of these treatments affected the glomerular filtration rate. Four months after the end of acetaminophen treatment, the renal changes had almost completely disappeared in the rats which had received the analgesic alone. Those continuously exposed to Cd had developed slight tubular damage, as evidenced by an increased urinary excretion of beta 2-microglobulin and beta-N-acetylglucosaminidase. By contrast, rats pretreated with acetaminophen for 2 months and exposed to Cd showed a marked increase in urinary excretion of albumin and beta 2-microglobulin, suggesting an interaction between both treatments. At the end of the study, only the interaction with beta 2-microglobulin excretion was still evident; that with the urinary excretion of beta-N-acetylglucosaminidase and albumin having been masked by the chronic progressive nephrosis affecting most animals at that stage. As acetaminophen had no effect on the renal accumulation of Cd, it may be concluded that pretreatment with this analgesic at a dose causing slight tubular dysfunction renders rat kidney more sensitive to the nephrotoxic action of Cd. This observation may be of clinical relevance for population groups occupationally or environmentally exposed to Cd.

The effect of atrial natriuretic factor on urinary albumin and ??; 2-microglobulin excretion in man

The effect of a 20-min infusion of atrial natriuretic factor (ANF) 99-126, 0.4 microgram/kg per min, on both urinary albumin and beta 2-microglobulin excretion was examined in nine normal male subjects during stable water diuresis. ANF caused a rise in urinary albumin in excretion (from 4.19 +/- 0.66 to 13.49 +/- 3.07 ng/min, P less than 0.01) without any significant change in either creatinine clearance of beta 2-microglobulin excretion. These findings suggest that ANF may enhance glomerular permeability to albumin in man.

Microalbuminuria and Hypertension in Long-Term Renal Donors

In order to determine whether the proteinuria observed in some renal donors was glomerular or tubular in origin, and to determine whether creatinine clearance was an accurate index of glomerular filtration rate (GFR) in subjects with reduced nephron mass, 29 donors were evaluated 9-18 years after uninephrectomy. Results were compared with those in 31 age-, sex-, and race-matched controls evaluated at the same time. Mean creatinine clearance (Ccreat) in donor was 78% that of controls, which was similar to the 85% ratio of inulin clearance (Cin) in donors compared with that of controls. Furthermore, the ratio of Ccreat/Cin was similar in both donors and controls. One third of the renal donors had an elevated albumin excretion compared with controls (microalbuminuria [12-220 mg/24 hr] in seven patients; 301 and 1084 mg/24 hr in two patients). There was no correlation between albuminuria and blood pressure, nor was there a demonstrable clinical cause for the albuminuria in most patients. In contrast to these results, excretion of beta-2 microglobulin, an index of tubular proteinuria, was normal in all but one patient. The prevalence of hypertension was higher in donors compared with the expected prevalence adjusted for age, sex, and race. These results verify that creatinine clearance is a reliable measure of GFR in long-term renal donors. They also demonstrate an increased frequency of glomerular proteinuria and hypertension in renal donors. Despite these mild abnormalities, GFR is well preserved for up to 18 years postuninephrectomy.

Prednisolone can increase glomerular permeability to proteins in nephrotic syndrome

In patients with a nephrotic syndrome administration of prednisolone causes an increase of proteinuria. To elucidate the mechanism of this effect we have studied the acute proteinuric effect of prednisolone, 125 to 150 mg intravenously, in nine patients (7 M, 2F) with a nephrotic syndrome. Mean age (+/- SD) of the patients was 53 +/- 6 years, mean endogenous creatinine clearance 104 +/- 30 ml/min, and mean proteinuria 7.7 +/- 3.0 g/24 hr. After administration of prednisolone, urinary total protein excretion rose in all patients from a mean (+/- SEM) of 4.89 +/- 0.59 mg/min before to 9.09 +/- 0.99 mg/min at five hours after administration (P less than 0.01). Glomerular filtration rate (inulin clearance), effective renal plasma flow (PAH clearance), and filtration fraction did not change significantly. The increases of urinary excretion of albumin (median %: +92%), IgG (median %: +88%), and transferrin (median %: +76%) were comparable and correlated significantly. Urinary excretion of beta 2-microglobulin did not change significantly however. We conclude that intravenous administration of prednisolone to patients with a nephrotic syndrome causes an increase in urinary protein excretion rate which cannot be explained by changes in renal hemodynamics or tubular protein reabsorption, and which therefore must be the result of a change in glomerular permselectivity characteristics.

Urinary growth hormone levels measured by ultrasensitive enzyme immunoassay in patients with renal insufficiency.

An ultrasensitive enzyme immunoassay was used to measure urinary GH levels in patients with renal insufficiency and normal subjects. Urinary GH excretion varied widely, but was significantly higher (P less than 0.01) in patients with renal insufficiency (median, 339; range, 2-17,000 ng/day) than in normal subjects (5.4; 1.2-15 ng/day). Urinary GH excretion correlated positively with urinary beta 2-microglobulin excretion (r = 0.79; P less than 0.001) and negatively with creatinine clearance (r = -0.83; P less than 0.001). Gel chromatography of urine from patients with renal insufficiency revealed a major peak of urinary GH corresponding to a mol wt of 22K, that of pituitary GH. These findings suggest that the kidneys play an important role in the catabolism of GH and that urinary GH may reflect, at least in part, renal function as well as hypothalamo-pituitary function.

Renal clearance of pancreatic and salivary amylase relative to creatinine clearance in patients with renal disease and proteinuria.

To study the charge-selective properties of the glomerular filter in renal disease, we measured the fractional clearance, relative to creatinine clearance (ECC), of the amylase isoenzymes pancreatic amylase and salivary amylase, which have identical size but different charge. In 63 healthy subjects the mean (and SD) fractional excretion of pancreatic amylase, 4.07% (1.24%), was fourfold that of salivary amylase: 1.02% (0.54%). For 29 patients with renal disease and proteinuria, the mean fractional excretion of pancreatic amylase was significantly lower, 3.31% (1.94%), and that of salivary amylase significantly higher, 2.06% (1.41%), than in controls. In these patients, fractional excretions of both these isoenzymes were negatively correlated with urinary excretion of beta 2-microglobulin and ECC. Evidently, differences in clearances of pancreatic and salivary amylase are a consequence of differences in charge-related glomerular filtration. The relative increase of salivary amylase clearance in patients with renal disease and proteinuria is most probably caused by a loss of the charge-selective properties of the glomerular basement membrane.

Indirect evidence of glomerular/tubular mixed-type postexercise proteinuria in healthy humans.

Hypothetical mechanisms have been postulated to explain the presence of proteins in urine after severe exercise. Recently, it has been shown that several amino acids inhibit tubular protein reabsorption. Seven healthy men, hyperhydrated, were studied during a 2-min bicycle exercise at supramaximal load. The subjects were tested without or with lysine perfusion (0.4 g/kg body wt iv). In both testing conditions, blood lactate increased to 13.8 mmol/l. Total protein urinary excretion increased to 1.10 and 1.67 mg/min, without and with lysine perfusion, compared with 79 micrograms/min at rest. In the meantime, albumin excretion increased 48- and 74-fold, respectively, while beta 2-microglobulin excretion increased 97- and 1,043-fold compared with basal values. The renal clearance of albumin increased to 8.4 microliters/min without lysine and to 12.0 microliters/min with lysine perfusion (rest 0.18). beta 2-Microglobulin clearance increased to 10.0 and 39.3 ml/min, respectively (rest 0.05). These data clearly demonstrate that postexercise proteinuria is of mixed type after exhaustive short-term exertion. Both increased glomerular permeability and partial tubular reabsorption inhibition to proteins appear to be involved.

Role of hypervolemia and renin in the blood pressure control of patients with pyelonephritis renal scarring.

Patients with pyelonephritic renal scarring are at risk of developing renal failure and hypertension. We studied glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction (FF), systolic (SBP) and diastolic (DBP) blood pressure, fractional sodium, potassium and phosphate excretion, peripheral renin activity (PRA), plasma aldosterone (p-Aldo), urinary albumin excretion (U-Alb) and urinary beta 2-microglobulin excretion (beta 2-M) in hydropenia and during transition to 3% volume expansion with isotonic saline infusion in 22 female patients with renal scarring due to pyelonephritis and 9 healthy controls. The patients had significantly lower GFR, higher SBP and higher PRA in hydropenia, but there was no significant difference in RPF, FF, DBP or p-Aldo. After volume expansion, SBP, DBP, PRA and p-Aldo were significantly higher in patients than in controls. Transition to 3% volume expansion was associated with a similar increase in SBP in both patients and controls, whereas DBP increased significantly more in the patients (p less than 0.01). Volume expansion resulted in a significant suppression of PRA and p-Aldo in both patients and controls. The patients with renal scarring had the same capacity to excrete sodium and water during transition to volume expansion as the healthy controls. The renin-aldosterone system seems abnormally activated and is probably more important than hypervolemia in the development of hypertension in this group of patients.

Relationship between urine beta-2-microglobulin and platinum levels during cisplatin treatment

We evaluated whether urine beta 2-microglobulin (beta 2M) excretion as a function of nephrotoxicity correlated with plasma and urine platinum levels in patients receiving cisplatin. Thirty-one patients had urine platinum measurements in urine samples collected at 0 to 6 and 6 to 24 h after cisplatin administration, 25 of these patients had serial plasma platinum measurements. Sixteen of the 31 patients had an increase in urine beta 2M. A significant correlation was obtained between urine platinum and beta 2M in the 6- to 24-h samples (r = 0.61, p less than 0.02). The mean plasma platinum levels were higher (12.6 +/- 6.1 mumol/L) in the patients with an increase in urine beta 2M compared to those patients with no change in beta 2M (6.8 +/- 4.1 mumol/L) (p less than 0.02). Our study indicates that tubular damage occurs within 24 h after cisplatin administration and that the damage correlates with urine platinum levels.

Studies of Enzymuria and β2-Microglobulinuria in Patients Receiving Prophylactic Cefotaxime in Obstetric and Gynaecological Surgery

Increased urinary excretion of beta 2-microglobulin and certain enzymes, for example leucine aminopeptidase (LAP) and N-acetyl-beta-D-glucosaminidase (NAG), produces sensitive markers of damage to renal tubular cells. These markers were monitored in patients undergoing obstetric and gynaecological surgery who received cefotaxime for 5 days. Slight increased activity in NAG and beta 2-microglobulin was observed in some patients 3 to 5 days after surgery. However, no changes of significance were found in levels of urinary LAP and NAG. During cefotaxime treatment, urinary beta 2-microglobulin in the group of abdominal hysterectomy increased slightly. In most cases renal side effects are negligible and cannot be detected by these tests. These results indicate that administration of cefotaxime in obstetric and gynaecological surgery does not produce cumulative renal tubular toxicity.

Measurement of Thyroid Stimulating Hormone(TSH) in Human Urine.

Using a highly sensitive and specific immunoradiometric assay kit for human TSH, we measured TSH concentrations in unprocessed urines in normal subjects, in patients with primary hypothyroidism, and patients with renal disease. In five of ten normal subjects TSH was detectable in urine samples (less than 20-69 microU/day). In five patients with hypothyroidism, the urinary TSH excretion was increased. In seven out of ten patients with nephrotic syndrome, eight out of nine patients with chronic renal failure and two patients with tubular dysfunction, the urinary TSH excretion was increased. The urinary TSH excretion correlated significantly with both urinary protein excretion and urinary beta 2-microglobulin excretion. These results suggest that the renal handling of TSH involves both glomerular filtration and tubular re-absorption, and that urinary TSH excretion is increased when serum TSH is increased and either glomerular or tubular function is impaired.

Alanine aminopeptidase and beta 2-microglobulin excretion in patients receiving vancomycin and gentamicin.

The effects of vancomycin, gentamicin, and combination vancomycin-gentamicin treatments on alanine aminopeptidase (AAP) and beta 2-microglobulin (beta 2M) elimination in 30 hospitalized patients were assessed and compared with elimination in a control group. Twenty-four-hour urine excretion values for AAP and beta 2M were determined on treatment day 1 and day 5 for patients receiving the three treatment regimens and for the control group. AAP excretion values for the vancomycin-treated group were not found to be statistically different from those of the control group. Both the gentamicin and the vancomycin-gentamicin groups had statistically higher AAP excretion values on treatment day 1 as well as on treatment day 5 when compared with the vancomycin and control groups. AAP excretion on day 5 of treatment was highest for the vancomycin-gentamicin group. Overall, beta 2M elimination was variable in all treatment groups. Although the beta 2M values were elevated as early as day 1 in all treatment groups, they were significantly elevated only in the vancomycin-gentamicin group on day 1 and only in the gentamicin group on day 5 compared with the vancomycin and the control groups. AAP appears to be a sensitive indicator of renal tubular damage. The combination of vancomycin and gentamicin results in greater AAP excretion than does either agent alone.

Evaluation of the nephrotoxic potential of styrene in man and in rat.

The urinary excretion of beta 2-microglobulin, retinol-binding protein and albumin was measured in 65 workers exposed to styrene at levels averaging 50 percent of the current threshold limit value (215 mg/m2) for 1-13 years (mean: 6 years). By comparison with a control group matched for age and socioeconomic status, no significant difference was observed in the urinary excretion of proteins. In rats, styrene was weakly nephrotoxic. No functional or morphological renal change could be disclosed in rats exposed to 565 mg of styrene/m3, 5 days/week for 13 weeks. The repeated i.p. injection of 1 g styrene/kg (1/5 of oral LD50) for 10 days induced only a slight tubular dysfunction as evidenced by a 5-fold increase in beta 2-microglobulinuria. Altogether, these epidemiological and experimental data suggest that the current threshold limit value for styrene (215 mg/m3) proposed by the American Conference of Governmental and Industrial Hygienists does not entail any risk of renal toxicity.

Occupational exposure to cadmium and kidney dysfunction.

Investigations were carried out in an alkaline battery factory. The study group consisted of 102 persons and the control group of 85 persons. Cadmium in blood (Cd-B) and cadmium in urine (Cd-U), as well as beta 2-microglobulin (B2-M), retinol binding protein (RBP), amino acids in urine were determined. Exposure to cadmium was high; Cd-B and Cd-U concentrations were higher than recommended, 10 micrograms/l and 10 micrograms/g creat. In 65% and 56% of workers, respectively. Excretion of B2-M and RBP in urine was higher than the accepted upper limits of 380 and 130 micrograms/g creat. in about 20% of the workers. A significant correlation was observed between: log Cd-U.log Cd-B (r = 0.85), log B2-M.log RBP (r = 0.66), log Cd-U.log B2-M (r = 0.52), and log Cd-U.log RBP (r = 0.55). To evaluate the admissible period of occupational exposure to cadmium, an integrated exposure index (Cd-B x years of exposure) is proposed. According to the dose-response relationship, an increase of low molecular protein excretion in urine can be expected in 10% of the cases at Cd-U amounting to 10 to 15 micrograms/g creat. and Cd-B x years of about 300 to 400.

Elevation of urinary trehalase activity in patients of itai-itai disease.

The elevation of urinary trehalase activity in patients of itai-itai disease was examined. Urinary trehalase was correlated with tubular reabsorption of phosphorus (%TRP): the lower the trehalase activity, the worse was %TRP. Furthermore, this activity was inversely correlated with urinary glucose and urinary total protein. In itai-itai disease, the excretion of beta 2-microglobulin seems to be maximal, and urinary trehalase activity was low in the latter stages of the disease. It is inferred that itai-itai disease produces extremely severe tubular damage as well as glomerular dysfunction.

Endogenous overnight creatinine clearance compared with 51Cr-EDTA clearance during the menstrual cycle.

Fourteen healthy women aged 21-41 years, who did not take oral contraceptives and who all had ovulatory cycles, were examined once in the follicular phase and once in the luteal phase of a single menstrual cycle. The glomerular filtration rate (51Cr-EDTA clearance) increased from the follicular to the luteal phase by a median of 7.0% (95% confidence interval: 0.7-10.3%). Endogenous overnight (22.00-08.00 hours) creatinine clearance increased by a median of 7.3% (95% confidence interval: 1.0-14.6%). The urinary creatinine excretion rate also increased with a median of 7.3% (95% confidence interval: 1.5-11.9%) whereas the serum concentrations of creatinine and beta 2-microglobulin, urine flow and urinary excretion rate of urea did not change. The results confirm previous observations of an increase in creatinine clearance in the luteal phase of the menstrual cycle and indicate that the increase in overnight creatinine clearance reflects a true change in glomerular filtration rate.

The proteinuria of industrial lead intoxication

Studies of protein excretion were undertaken in seven males, aged 35-42 years, who had more than 5 years exposure to industrial lead and had clinically established Pb intoxication. Heavy metal intoxication with Cd and Hg causes proximal tubular abnormalities, i.e., aminoaciduria, glycosuria, phosphaturia. Similar abnormalities occur in Pb intoxication except that the nature of the proteinuria remains controversial. Studies of urinary proteins included 24-hr urine protein excretion, dextran gel separations, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and beta 2 microglobulin (B2M) measurements. Creatinine clearances, and serum B2M concentrations were normal. Urine total protein distribution by SDS-PAGE and the B2M excretion rate were also normal. These data imply that the nephrotoxicity of Cd and Hg are different than that of Pb. We speculate on what might account for this difference. This study suggests that when examining a population exposed to Pb, the finding of tubular proteinuria should alert investigators to search for the presence of other toxic agents.

Pharmacokinetics and nephrotoxicity of continuous intravenous infusion of gentamicin in low birth weight infants

We evaluated the pharmacokinetics and renal effects of continuous intravenous infusion of gentamicin compared with multiple-dose therapy given in equivalent daily amounts. Nine infants (mean gestational age 34.7 weeks, mean birth weight 2107 gm) were given intermittent injections of gentamicin and 10 infants (mean gestational age 34.8 weeks, mean birth weight 2078 gm) received gentamicin by continuous infusion. Comparison of gentamicin pharmacokinetic data revealed a larger volume of distribution and AUC, prolonged terminal t1/2, and slower total body clearance of the drug in those infants receiving gentamicin by continuous infusion. During and after therapy the fractional excretion of sodium was significantly increased in the continuous infusion group. After treatment the creatinine clearance and excretion of beta 2-microglobulin were significantly lower in the continuous therapy group. Our results indicate that infants receiving gentamicin by constant infusion are at higher risk of nephrotoxicity. The extent of this nephrotoxic hazard remains to be determined.